Are Revolutionary New Drugs on the Horizon to Reduce CV Risks?

What you “need to know” about PCSK9 Inhibitors

Several new drugs that significantly reduce low density lipoprotein (LDL) cholesterol levels have recently been recommended by experts for approval by the Federal Drug Administration (FDA). Many are optimistic about the approval of alirocumab (suggested trade name Praluent) on July 24th and evolocumab (suggested trade name Repatha) on August 27th. Note the suffix “mab” which stands for monoclonal antibodies. This class of medications is currently being used in the treatment of non-cardiovascular conditions by gastroenterologists, oncologists, and rheumatologists and is known particularly for being able to very specifically target their effect with little off-target effects. Both of these PCSK9 inhibitors are “fully human” monoclonal antibodies which bodes well for them.

Pro-protein convertase subtilisin-like Kexin type 9 (PCSK9 for short!) inhibitors specifically target PCSK9, the enzyme that attaches to low-density lipoprotein (LDL) receptors and leads to their degradation, stopping them from their return to the surface of the cell to remove more LDL from the blood. Although PCSK9 inhibitors have to be given via subcutaneous injection, once every 2 to 4 weeks, they have been shown to lower LDL cholesterol in the 60% range, even on top of statin therapies and/or other LDL lowering agents.1,2 Patients with familial hypercholesterolemia, for example, can reduce LDL cholesterol levels from around 300 mg/dL to 100 mg/dL when these drugs are added.

Some forecasts that the PCSK9 inhibitors will be as revolutionary to cardiovascular risk reduction therapy as the statins were when first introduced in the late 1980s. Excitement was tremendous when data from ODYESSY Long-Term (n=2341) and OSLER (n=4465) results showed reductions of LDL cholesterol from an average of 120mg/dL to 48 mg/dL or baseline LDL levels >70mg/dL to 48mg in these trials, respectively.1,2 Additionally, data from both trials suggested significant reductions in clinical events (e.g., death, heart attack, fatal or non-fatal strokes, revascularization, etc.).1,2 Though neither of these trials was powered to look at hard clinical outcomes, one showed event reduction in a post-hoc analysis and the other in an unblinded extension study. There are several very large trials currently underway that are specifically designed to look at hard cardiovascular outcomes, but they are not expected to be completed until 2017.

Although the safety and tolerability of these agents is looking good to most and subjects who have had LDL cholesterol levels <25mg for at least a year appear to be doing well, what the FDA will require for approval and indications for their use is unclear. Others are not so sure these drugs will be approved to lower LDL without clinical outcomes or that they will be blockbuster hits because they are injectable and may be quite expensive.